OP0129 REPORTED CONGENITAL MALFORMATIONS AFTER EXPOSURE TO NON-TNF-Α INHIBITORS: A RETROSPECTIVE COMPARATIVE STUDY IN EUDRAVIGILANCE DATABASE
Authors: N. Ghalandari, H. J. M. J. Crijns, J. Bergman, R. Dolhain, E. van Puijenbroek, J. Hazes
Journal: Annals of the Rheumatic Diseases (2022)

Background Tumor necrosis factor-α inhibitors (TNFis) such as certolizumab pegol (CZP), are a subgroup of biologics, which have shown no increase in risk of congenital malformations (CMs) after use during pregnancy. (1) However, for the subgroup of non-TNFis, very scarce data is available. Objectives To evaluate the number and nature of reported CMs after intrauterine exposure to non-TNFis compared to CZP, in Eudravigilance database. Methods A retrospective comparative study in EudraVigilance database was conducted. Reports of all pregnancies exposed to non-TNFis and CZP, were extracted. Multiple versions of a unique case, pregnancies with unknown outcome, paternal exposures, CMs due to known genetic abnormalities, and cases exposed only via breast milk were excluded. Odd ratios for CMs were calculated for each non-TNFi, with CZP as reference group. Due to limitations of pharmacovigilance databases, such as possibility of under-reporting normal outcomes and information bias (2), in consultation with a clinical geneticist, CM patterns were compared between non-TNFi and CZP groups. Results In total 851 non-TNFi and 1179 CZP exposed pregnancy reports were included. Numerical differences for CMs after exposure to non-TNFis were not statistically significant except for belimumab and vedolizumab (Table 1). Table 1. Reported number, crude and adjusted ORs [95%CIs] for major and minor CMs and TOPFAs after intrauterine exposure to non-TNFis compared to CZP Medication Reported CMs and TOPFAs, n/N (%) Crude ORs [95%CIs], Adjusted ORs (for maternal age) [95%CIs], Stratified ORs (teratogen unexposed cases only) [95%CIs] * Certolizumab pegol 95/1179 (8.05) Reference Reference Reference Abatacept 2/64 (3.12) 0.36 [0.08, 1.52] 0.35 [0.08, 1.47] 0.69 [0.16, 2,96] Anakinra 3/20 (15.00) 2.01 [0.57, 6.99] 2.81 [0.77, 10.20] 3.39 [0.91, 12.63] Belimumab 17/93 (18.27) 2.55 [1.44, 4.49] 2.63 [1.40, 4.93] 2.65 [1.35, 5.20] Ixekizumab 1/29 (3.44) 0.40 (0.05, 3.02] 0.39 [0.05, 2.96] 0.42 [0.05, 3.16] Rituximab 8/57 (14.03) 1.86 [0.85, 4.04] 2.47 [1.05, 5.80] 2.55 [0.94, 6.95] Secukinumab 4/128 (3.12) 0.36 [0.13, 1.01] 0.34 [0.10, 1.11] 0.37 [0.11, 1.19] Tocilizumab 10/124 (8.06) 1.00 [0.50, 1.97] 0.79 [0.37, 1.68] 0.62 [0.22, 1.76] Ustekinumab 19/215 (8.83) 1.10 [0.66, 1.85] 0.92 [0.51, 1.66] 1.01 [0.56, 1.82] Vedolizumab 23/113 (20.35) 2.91 [1.76, 4.82] 2.66 [1.53, 4.61] 2.27 [1.24, 4.15] OR: odds ratio; CI: confidence interval; CM: congenital malformation; TOPFA: termination of pregnancy due to foetal anomaly anomaly. *After adjusting for maternal age, stratified ORs are presented for patients who had no reported teratogen exposure during pregnancy. Pattern of CMs were reviewed by a clinical geneticist. Except for vedolizumab, no specific CM patterns were observed. For vedolizumab four cases of corpus callosum agenesis (CCA) were reported (versus null in CZP and other investigated non-TNFis). Three of the CCA cases were associated with other neurological CMs such as a neural tube defect, microcephaly and polymicrogyria. This indicates that the reported CCAs may have been related to undiagnosed genetic alterations or were associated with underlying maternal disease, although a definite relationship cannot be ruled out. Conclusion Except for vedolizumab, no special safety signal was identified regarding occurrence of CMs after exposure to non-TNFis. Based on available information, no firm conclusions can be made regarding observed CCA cases in vedolizumab group. References [1]EuropeanMedicinesAgency, Summary of Product Characteristics (SmPC) Certolizumab pegol (Cimzia). European Medicines Agency 2021. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001037/WC500069763.pdf . [2]Klein K, Scholl JHG, De Bruin ML, van Puijenbroek EP, Leufkens HGM, Stolk P. When More Is Less: An Exploratory Study of the Precautionary Reporting Bias and Its Impact on Safety Signal Detection. Clin Pharmacol Ther. 2018;103(2):296-303. Acknowledgements We would like to thank C. Zaccaria and L. Piccolo for their contributions to access and interpreting data from EudraVigilance database. The views expressed in this article are the personal views of the author(s) and may not be understood or quoted as being made on behalf of or reflecting the position of the regulatory agency/agencies or organizations with which the author(s) is/are employed/affiliated. Disclosure of Interests Nafise Ghalandari: None declared, Hubertina Johanna Maria Josephina Crijns: None declared, Jorieke Bergman: None declared, Radboud Dolhain Speakers bureau: UCB, Roche, Abbvie, Genzyme, Novartis, Lilly, Grant/research support from: RJEM. Dolhain, MD, PhD received an unrestricted grant from UCB Pharma B.V, Dutch Arthritis Association and Galapagos., Eugène van Puijenbroek: None declared, Johanna Hazes: None declared